Undecaprenyl phosphate

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Undecaprenyl phosphate
Undecaprenyl phosphate.png
Names
IUPAC name
[(2E,6E,10E,14E,18E,22E,26E,30E,34E,38E)-3,7,11,15,19,23,27,31,35,39,43-undecamethyltetratetraconta-2,6,10,14,18,22,26,30,34,38,42-undecaenyl] dihydrogen phosphate
Other names
Undecaprenyl phosphate; 3,7,11,15,19,23,27,31,35,39,43-Undecamethyl-2,6,10,14,18,22,26,30,34,38,42-tetratetracontaun decaen-1-ol, dihydrogen phosphate
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
KEGG
PubChem CID
  • InChI=1S/C55H91O4P/c1-45(2)23-13-24-46(3)25-14-26-47(4)27-15-28-48(5)29-16-30-49(6)31-17-32-50(7)33-18-34-51(8)35-19-36-52(9)37-20-38-53(10)39-21-40-54(11)41-22-42-55(12)43-44-59-60(56,57)58/h23,25,27,29,31,33,35,37,39,41,43H,13-22,24,26,28,30,32,34,36,38,40,42,44H2,1-12H3,(H2,56,57,58)/b46-25+,47-27+,48-29+,49-31+,50-33+,51-35+,52-37+,53-39+,54-41+,55-43+
    Key: UFPHFKCTOZIAFY-RDQGWRCRSA-N
  • CC(=CCC/C(=C/CC/C(=C/CC/C(=C/CC/C(=C/CC/C(=C/CC/C(=C/CC/C(=C/CC/C(=C/CC/C(=C/CC/C(=C/COP(=O)(O)O)/C)/C)/C)/C)/C)/C)/C)/C)/C)/C)C
Properties
C55H91O4P
Molar mass 847.303 g·mol−1
Related compounds
Related compounds
C55-isoprenyl pyrophosphate
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Undecaprenyl phosphate (UP), also known lipid-P, bactoprenol [1] and C55-P., [2] is a molecule with the primary function of trafficking polysaccharides across the cell membrane, largely contributing to the overall structure of the cell wall in Gram-positive bacteria. In some situations, UP can also be utilized to carry other cell-wall polysaccharides, but UP is the designated lipid carrier for peptidoglycan. During the process of carrying the peptidoglycan across the cell membrane, N-acetylglucosamine and N-acetylmuramic acid are linked to UP on the cytoplasmic side of the membrane before being carried across. [3] UP works in a cycle of phosphorylation and dephosphorylation as the lipid carrier gets used, recycled, and reacts with undecaprenyl phosphate. This type of synthesis is referred to as de novo synthesis where a complex molecule is created from simpler molecules as opposed to a complete recycle of the entire structure. [3]

Contents

The synthesis of UP differs between Gram-negative and Gram-positive bacteria. In Gram-positive bacteria, undecaprenol is found in vast quantities, which is then phosphorylated into UP. For Gram-negative bacteria however, there has yet to be any indication that they contain any undecaprenol at all. Instead of having an undecaprenol be phosphorylated, it appears that instead, Gram-negative bacteria undergo a dephosphorylation of undecaprenyl diphosphate which is catalyzed by both a type-2 phosphatidic acid, phosphatase homologue, and a BacA homologue. [4]

Undecaprenyl phosphate is also known to be the "Universal Glycan Lipid Carrier". When UP is inhibited, the peptidoglycan synthesis is interrupted and it could lead to cell lysis. Furthermore, UP is involved in the metabolism of many cellular processes that can potentially be targeted by antibiotics. Also, it is common for bacteria to use UP to translocate glycan; however, certain bacteria do not use undecaprenyl phosphate as a glycan translocator. [3]

Biosynthetic processes

Peptidoglycan synthesis

UP is involved in transporting peptidoglycan subunits from the cytoplasmic face of the cell membrane to the periplasmic or extracellular surface. [2]

In the process, UP (also called lipid-P) complexes with UDP-N-acetylmuramic acid pentapeptide (UDP-NAM pentapeptide) to form lipid I, displacing UMP. From there, lipid I complexes with N-acetyl glucosamine (NAG) to form lipid II. Lipid II then is flipped across the membrane by a flippase to the outside leaflet of the cell membrane. [5] [6] The NAG-NAM pentapeptide subunit is then added onto the growing peptidoglycan chain, leaving behind undecaprenyl diphosphate. The extra phosphate on undecaprenyl diphosphate is cleaved by a pyrophosphatase and UP is then recycled to the cytoplasmic face of the cell membrane. [2]

O-antigen synthesis in lipopolysaccharide assembly

UP also serves as the lipid transporter for the O-antigen component of lipopolysaccharide. It is supposed that sugars are assembled into O-antigen subunits directly on UP on the cytoplasmic surface of the cell membrane. Then the UP-O-antigen subunit gets flipped to the other side of the membrane, where similar UP-O-antigen subunits interact and aggregate the O-antigen subunits into repeating-subunit chains, leaving undecaprenyl diphosphate behind. Again undecaprenyl phosphate is recycled by a pyrophosphatase and flipped to the cytoplasmic face again. [7]

Inhibition

UP is a valuable transporter for cell wall equipment. That being said, the components necessary for the proper UP functioning can be inhibited, restricting the aiding of cell wall synthesis. As a result, the bacteria's structure is compromised, and its ability to combat lysing is lost. [2] On a larger scale, this is helpful when fighting, or preventing bacterial infections.

Bacitracin is an example of one of these antibiotics. It is a generic topical cream used for "cuts, scrapes, and burns", possessing "bacteriostatic and bactericidal properties". [8] The process is accomplished by targeting and inhibiting the enzyme used to renew UP—membrane-bound undecaprenyl phosphatase hydrolyzing undecaprenyl diphosphate to UP. This renewal process is crucial for maintaining the flow of lipid I and lipid II across the membrane, and without it, the cell wall synthesis process is halted. [2]

Clomifene, a medication used to treat infertility in women, is another UP inhibitor discovered in the last decade. It has a similar process of cell wall disruption as bacitracin, resulting with lysis of cells. [9] [10]

While Bacitracin and clomiphene are not the only inhibitors out there, they are two on the evolving list that have been experimentally proven to inhibit pyrophosphatase.

Related Research Articles

<span class="mw-page-title-main">Gram-negative bacteria</span> Group of bacteria that do not retain the Gram stain used in bacterial differentiation

Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidoglycan cell wall sandwiched between an inner membrane (cytoplasmic), and an outer membrane.

Peptidoglycan or murein is a unique large macromolecule, a polysaccharide, consisting of sugars and amino acids that forms a mesh-like peptidoglycan layer (sacculus) that surrounds the bacterial cytoplasmic membrane. The sugar component consists of alternating residues of β-(1,4) linked N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM). Attached to the N-acetylmuramic acid is an oligopeptide chain made of three to five amino acids. The peptide chain can be cross-linked to the peptide chain of another strand forming the 3D mesh-like layer. Peptidoglycan serves a structural role in the bacterial cell wall, giving structural strength, as well as counteracting the osmotic pressure of the cytoplasm. This repetitive linking results in a dense peptidoglycan layer which is critical for maintaining cell form and withstanding high osmotic pressures, and it is regularly replaced by peptidoglycan production. Peptidoglycan hydrolysis and synthesis are two processes that must occur in order for cells to grow and multiply, a technique carried out in three stages: clipping of current material, insertion of new material, and re-crosslinking of existing material to new material.

<span class="mw-page-title-main">Teichoic acid</span>

Teichoic acids are bacterial copolymers of glycerol phosphate or ribitol phosphate and carbohydrates linked via phosphodiester bonds.

<span class="mw-page-title-main">Periplasm</span>

The periplasm is a concentrated gel-like matrix in the space between the inner cytoplasmic membrane and the bacterial outer membrane called the periplasmic space in gram-negative bacteria. Using cryo-electron microscopy it has been found that a much smaller periplasmic space is also present in gram-positive bacteria, between cell wall and the plasma membrane.

The cell envelope comprises the inner cell membrane and the cell wall of a bacterium. In gram-negative bacteria an outer membrane is also included. This envelope is not present in the Mollicutes where the cell wall is absent.

<span class="mw-page-title-main">Bacitracin</span> Polypeptide Antibiotic (Gram Positive Bacteriacide)

Bacitracin is a polypeptide antibiotic. It is a mixture of related cyclic peptides produced by Bacillus licheniformis bacteria, that was first isolated from the variety "Tracy I" in 1945. These peptides disrupt gram-positive bacteria by interfering with cell wall and peptidoglycan synthesis.

<span class="mw-page-title-main">Bacterial outer membrane</span> Plasma membrane found in gram-negative bacteria

The bacterial outer membrane is found in gram-negative bacteria. Its composition is distinct from that of the inner cytoplasmic cell membrane - among other things, the outer leaflet of the outer membrane of many gram-negative bacteria includes a complex lipopolysaccharide whose lipid portion acts as an endotoxin - and in some bacteria such as E. coli it is linked to the cell's peptidoglycan by Braun's lipoprotein.

<span class="mw-page-title-main">Penicillin-binding proteins</span> Class of proteins

Penicillin-binding proteins (PBPs) are a group of proteins that are characterized by their affinity for and binding of penicillin. They are a normal constituent of many bacteria; the name just reflects the way by which the protein was discovered. All β-lactam antibiotics bind to PBPs, which are essential for bacterial cell wall synthesis. PBPs are members of a subgroup of enzymes called transpeptidases. Specifically, PBPs are DD-transpeptidases.

The bacterium, despite its simplicity, contains a well-developed cell structure which is responsible for some of its unique biological structures and pathogenicity. Many structural features are unique to bacteria and are not found among archaea or eukaryotes. Because of the simplicity of bacteria relative to larger organisms and the ease with which they can be manipulated experimentally, the cell structure of bacteria has been well studied, revealing many biochemical principles that have been subsequently applied to other organisms.

In enzymology, an undecaprenyl-diphosphatase (EC 3.6.1.27) is an enzyme that catalyzes the chemical reaction

Peptidoglycan glycosyltransferase is an enzyme used in the biosynthesis of peptidoglycan. It transfers a disaccharide-peptide from a donor substrate to synthesize a glycan chain.

<span class="mw-page-title-main">Bactoprenol</span> Chemical compound

Bactoprenol also known as dolichol-11 and C55-isoprenyl alcohol (C55-OH) is a lipid first identified in certain species of lactobacilli. It is a hydrophobic alcohol that plays a key role in the growth of cell walls (peptidoglycan) in Gram-positive bacteria.

C55-isoprenyl pyrophosphate is an essential molecule involved in construction of the bacterial peptidoglycan cell wall. It is a receptor found in the plasma membrane of bacteria that allows glycan tetrapeptide monomers synthesized in the cell cytoplasm to translocate to the periplasmic space.

UDP-N-acetylglucosamine—undecaprenyl-phosphate N-acetylglucosaminephosphotransferase is an enzyme with systematic name UDP-N-acetyl-alpha-D-glucosamine:ditrans,octacis-undecaprenyl phosphate N-acetyl-alpha-D-glucosaminephosphotransferase. This enzyme catalyses the following chemical reaction

Eleftheria terrae is a recently discovered Gram-negative bacterium. E. terrae is a temporary name for the organism, as it was only discovered in 2014 and is still undergoing scientific study. It was found to produce a previously unknown antibiotic named teixobactin. The discovery of E. terrae could represent a new age of antibiotics, as teixobactin is the first new antibiotic discovered since the synthetic era of the 1980s. Prior research has indicated that other uncultivable bacteria like E. terrae have potential in the development of new antimicrobial agents.

<span class="mw-page-title-main">Lipid II</span> Chemical compound

Lipid II is a precursor molecule in the synthesis of the cell wall of bacteria. It is a peptidoglycan, which is amphipathic and named for its bactoprenol hydrocarbon chain, which acts as a lipid anchor, embedding itself in the bacterial cell membrane. Lipid II must translocate across the cell membrane to deliver and incorporate its disaccharide-pentapeptide "building block" into the peptidoglycan mesh. Lipid II is the target of several antibiotics.

The bacterial murein precursor exporter (MPE) family is a member of the cation diffusion facilitator (CDF) superfamily of membrane transporters. Members of the MPE family are found in a large variety of Gram-negative and Gram-positive bacteria and facilitate the translocation of lipid-linked murein precursors. A representative list of proteins belonging to the MPE family can be found in the Transporter Classification Database.

The multidrug/oligosaccharidyl-lipid/polysaccharide (MOP) flippase superfamily is a group of integral membrane protein families. The MOP flippase superfamily includes twelve distantly related families, six for which functional data are available:

  1. One ubiquitous family (MATE) specific for drugs - (TC# 2.A.66.1) The Multi Antimicrobial Extrusion (MATE) Family
  2. One (PST) specific for polysaccharides and/or their lipid-linked precursors in prokaryotes - (TC# 2.A.66.2) The Polysaccharide Transport (PST) Family
  3. One (OLF) specific for lipid-linked oligosaccharide precursors of glycoproteins in eukaryotes - (TC# 2.A.66.3) The Oligosaccharidyl-lipid Flippase (OLF) Family
  4. One (MVF) lipid-peptidoglycan precursor flippase involved in cell wall biosynthesis - (TC# 2.A.66.4) The Mouse Virulence Factor (MVF) Family
  5. One (AgnG) which includes a single functionally characterized member that extrudes the antibiotic, Agrocin 84 - (TC# 2.A.66.5) The Agrocin 84 Antibiotic Exporter (AgnG) Family
  6. And finally, one (Ank) that shuttles inorganic pyrophosphate (PPi) - (TC# 2.A.66.9) The Progressive Ankylosis (Ank) Family
<span class="mw-page-title-main">Moenomycin family antibiotics</span> Antibiotic Family

First described in 1965, the moenomycins are a family of phosphoglycolipid antibiotics, metabolites of the bacterial genus Streptomyces. Moenomycin A is the founding member of the antibiotic family with the majority discovered by the end of the late 1970s.

The enterobacterial common antigen (ECA) is a carbohydrate antigen found in the outer membrane of many Enterobacterales species. The antigen is unanimously absent from other gram-negative and gram-positive bacteria. Aeromonas hydrophila 209A is the only organism outside of Enterobacterales that expresses the ECA. More studies are needed to explain the presence of the antigen in this species as no other strains of this species express the antigen. The ECA is a polysaccharide made of repeating units of trisaccharides. The functions of these units have very few proven functions. Some evidence indicates role in pathogenicity in the bacteria that present the ECA. There are three separate types of ECA these include ECAPG, ECALPS, and ECACYC, each have different lengths. The synthesis of the ECA is controlled by the wec operon and has a 12-step synthesis which is described below. Due to the lack of proven function of the ECA, any clinical significance is hard to define however, some evidence suggests that human serum has antibodies against ECA.

References

  1. ↑ TouzÉ, Thierry; Mengin-Lecreulx, Dominique (2008-02-12). Slauch, James M. (ed.). "Undecaprenyl Phosphate Synthesis". EcoSal Plus. 3 (1): ecosalplus.4.7.1.7. doi:10.1128/ecosalplus.4.7.1.7. ISSN   2324-6200. PMID   26443724.
  2. 1 2 3 4 5 White, David; Drummond, James; Fuqua, Clay (2012). The Physiology and Biochemistry of Prokaryotes (4th ed.). New York, New York: Oxford University Press. pp. 319–321. ISBN   978-0-19-539304-0.
  3. 1 2 3 Manat, Guillaume; Roure, Sophie; Auger, Rodolphe; Bouhss, Ahmed; Barreteau, Hélène; Mengin-Lecreulx, Dominique; Touzé, Thierry (2014-06-01). "Deciphering the Metabolism of Undecaprenyl-Phosphate: The Bacterial Cell-Wall Unit Carrier at the Membrane Frontier". Microbial Drug Resistance. 20 (3): 199–214. doi:10.1089/mdr.2014.0035. ISSN   1076-6294. PMC   4050452 . PMID   24799078.
  4. ↑ Kawakami, Naoki; Fujisaki, Shingo (2018-06-03). "Undecaprenyl phosphate metabolism in Gram-negative and Gram-positive bacteria". Bioscience, Biotechnology, and Biochemistry. 82 (6): 940–946. doi: 10.1080/09168451.2017.1401915 . ISSN   0916-8451. PMID   29198165. S2CID   13605619.
  5. ↑ Meeske, Alexander J.; Sham, Lok-To; Kimsey, Harvey; Koo, Byoung-Mo; Gross, Carol A.; Bernhardt, Thomas G.; Rudner, David Z. (2015-05-19). "MurJ and a novel lipid II flippase are required for cell wall biogenesis in Bacillus subtilis". Proceedings of the National Academy of Sciences of the United States of America. 112 (20): 6437–6442. Bibcode:2015PNAS..112.6437M. doi: 10.1073/pnas.1504967112 . ISSN   1091-6490. PMC   4443310 . PMID   25918422.
  6. ↑ Kuk, Alvin C. Y.; Hao, Aili; Lee, Seok-Yong (2022-06-21). "Structure and Mechanism of the Lipid Flippase MurJ". Annual Review of Biochemistry. 91: 705–729. doi:10.1146/annurev-biochem-040320-105145. ISSN   1545-4509. PMC   10108830 . PMID   35320686. S2CID   247628850.
  7. ↑ White, David (2012). The physiology and biochemistry of prokaryotes. James Drummond, Clay Fuqua (4th ed.). New York: Oxford University Press. pp. 323–324. ISBN   978-0-19-539304-0. OCLC   752472552.
  8. ↑ Nguyen, Rosalee; Khanna, Niloufar R.; Safadi, Anthony O.; Sun, Yan (2022), "Bacitracin Topical", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID   30725678 , retrieved 2022-10-06
  9. ↑ Lee, Da-Gyum; Hwang, Yoo-Hyun; Park, Eun-Jin; Kim, Jung-Hyun; Ryoo, Sung-Weon (2021-10-13). "Clomiphene Citrate Shows Effective and Sustained Antimicrobial Activity against Mycobacterium abscessus". International Journal of Molecular Sciences. 22 (20): 11029. doi: 10.3390/ijms222011029 . ISSN   1422-0067. PMC   8537717 . PMID   34681686.
  10. ↑ Farha, Maya A.; Czarny, Tomasz L.; Myers, Cullen L.; Worrall, Liam J.; French, Shawn; Conrady, Deborah G.; Wang, Yang; Oldfield, Eric; Strynadka, Natalie C. J.; Brown, Eric D. (September 2015). "Antagonism screen for inhibitors of bacterial cell wall biogenesis uncovers an inhibitor of undecaprenyl diphosphate synthase". Proceedings of the National Academy of Sciences. 112 (35): 11048–11053. Bibcode:2015PNAS..11211048F. doi: 10.1073/pnas.1511751112 . ISSN   0027-8424. PMC   4568241 . PMID   26283394.
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